Alcohol-Induced Sleepiness and Memory Function.

Alcohol has sedative, as well as performance and memory-impairing effects. Several independent lines of research indicate that alcohol-induced sleepiness may contribute to the observed memory and performance impairment. Such a link would imply that alcohol consumption in combination with other drugs or conditions that enhance sleepiness could increase the risk for alcohol-related impairment.

A lcohol is known to impair various performancedisruptive effects provide Finally, most people experience a circadian aspects of cognitive functioning, further support. The article also describes fluctuation with increased sleepiness over including learning and memory some of the neurotransmitter systems con the midday and increased alertness in the (Birnbaum and Parker 1977).
trolling sleep and wakefulness that are affect early evening. Alcoholinduced memory impairment has ed by alcohol and other sedative drugs and To assess sleepiness or alertness or the been studied extensively both by researchers that may underlie the association of sedation sedative effects of drugs, such as alcohol, and clinicians, partly because memory and memory impairment. Finally, some scientists have asked people to selfrate impairment has everyday practical conse important practical implications of the poten their sleepiness or have used standard quences for the affected patient. In addition, tial correlation between alcohol's sedative laboratory tests of performance. However, precise methods exist to assess memory and memoryimpairing effects are discussed. for the reasons stated above, selfratings functions. However, despite the large num of sleepiness or sedative drug effects may ber of studies on alcoholinduced memory be inaccurate (Roth et al. 1982). Similarly, impairment, there is little consensus about

WHAT IS SLEEPINESS?
performance tests sometimes are insensitive the specific components of memory affected to the effects of small doses of sedative by alcohol or about the neurobiological Like hunger and thirst, sleepiness is con drugs or low breath alcohol concentrations. mechanisms underlying alcohol's effects. sidered a basic physiological drive state. A method to assess sleepiness objec A useful method of conceptualizing It reflects the organism's need or pressure tively has been developed, however. This the way alcohol may affect memory is for sleep. Like other physiological drive method conceptually is based on an obser offered by Curran (1991). This concept states, the level of sleepiness is difficult to entails that mood, level of sleepiness/ assess. Despite a general tendency toward vation originating in the 19th century that alertness (or, as Curran describes it, increasing sleepiness after sleep loss, most as sleep loss progresses over time, people increasingly experience uncontrollable arousal), and memory all are interrelated.
sleep deprivation studies find some incon Alcohol is known to affect directly each of sistencies in the subjects' personal assess these factors. And by acting on one factor, ment of how sleepy they are (Monk 1991; TIMOTHY ROEHRS, PH.D., is director of re alcohol also can indirectly affect the other Roth et al. 1994 brief naps or microsleeps (Patrick and Gilbert 1896). In the Multiple Sleep Latency Test (MSLT), researchers quantify sleepi ness by giving subjects repeated opportu nities to fall asleep (Carskadon et al. 1986;Roth et al. 1994). Typically, four to five tests are conducted at 2hour intervals in a sleepconducive environment. Physiological recordings of the subject's brain waves and eye movements determine the exact moment of sleep onset. The time between lying down and sleep onset (i.e., the latency) is a measure of the subject's level of sleepiness. People with a high degree of sleepi ness (e.g., because they are totally de prived of sleep, have had insufficient sleep relative to their biological needs, or are suffering from sleep disorders) fall asleep rapidly when given the opportunity to sleep. These people have a short laten cy on the MSLT. For example, limiting sleeping time by limiting timeinbed (TIB) to 5 hours for several consecutive nights progressively decreases the sub jects' sleep latency over the test days (figure 1; ZwyghuizenDoorenbos et al. 1988). In people with longer TIB's or people who are treated successfully for a sleep disorder, sleep latency increases on the MSLT (i.e., they are more alert).
The MSLT also can measure the effects of stimulant and depressant drugs on sleepi ness . Stimulant drugs increase and depressant drugs decrease sleep latency in a dosedependent manner. For example, increasing doses of depressant drugs lead to systematic increases in sleepi ness as measured by the MSLT. Thus, the reliability and validity of the MSLT have been established under different experimen tal conditions ).

SLEEPINESS AND MEMORY IMPAIRMENT
A correlation between sleepiness and memory impairment already was observed in the last century when Patrick and Gilbert (1896) reported that after 72 hours of wake fulness, subjects were unable "to attend to a memory task." Subsequent systematic studies of sleep deprivation and sleep restriction in healthy people supported the association of sleep loss with memory loss (Dinges and Kribbs 1991).
MSLT studies of patients with different sleep disorders have helped to confirm that sleepiness, which is the consequence of sleep loss or sleep fragmentation (i.e., fre quent sleep interruptions), is the intervening variable causing the memory impairment: • Patients with sleep apnea syndrome stop breathing during their sleep and wake up to resume breathing, leading to sleep fragmentation. Standardized tests of neuropsychological function ing in these patients detect impairment on a range of cognitive functions, includ ing memory (Roehrs et al. in press). The extent of sleep fragmentation at night and the resulting daytime sleepi ness directly correlate with the extent of neuropsychological impairment (Roehrs et al. in press).
• Patients with narcolepsy, a sleep disor der with unknown causes, suffer from excessive daytime sleepiness as docu mented by short MSLT latencies. Fifty percent of the patients have memory lapses, and 80 percent of the patients report episodes of automatic behavior (i.e., an ongoing behavioral activity that the patient does not remember doing, such as missing freeway exits, driving through stop signs, or writing nonsense) (Aldrich 1992).
• Patients with chronic sleep restriction (i.e., their sleep is normal but their TIB is reduced by 1 to 2 hours per night relative to their biological needs) com plain about persistent daytime sleepi ness and have reduced sleep latency on the MSLT (Roehrs et al. 1983). Merrion and colleagues (1992) found that these patients also showed impairment on standardized neuropsychological tests, specifically on memory tests.
Memory development encompasses several processes, or phases, that occur when information is stored in the brain. One old and rather simplistic-but in this con text, sufficient-model of memory process ing distinguishes three phases of memory development (Lister et al. 1987). The first phase is the stimulus registration or acquisi tion phase, in which information is entered into shortterm memory. The second phase is the consolidation of information from shortterm into longterm memory (i.e., memory for more than 30 seconds). The third phase includes the retrieval of infor mation from longterm memory.
Sleepiness can interfere with all three phases of memory development. Elkin and Murray (1974) assessed sleepiness effects on the acquisition phase by studying sleepdeprived subjects who experienced uncontrollable microsleeps (i.e., sleep episodes of less than 15 seconds). During microsleeps, the subjects did not respond to a given stimulus, suggesting that they did not register the stimulus.
Other studies found that the process of sleep onset or increasing sleepiness also disrupts memory consolidation. In a study by Guilleminault and Dement (1977), subjects were presented with a stimulus at 1minute intervals as they were falling asleep. Even when stimulus registration was ascertained, the subjects' memory when they were awakened 10 minutes later decreased as the stimulus occurred closer to sleep onset. Other studies found a general slowing of cognitive functions as a conse quence of sleep loss (Dinges and Kribbs 1991). This may reflect a reduced informa tion consolidation or impaired retrieval of information from longterm memory.

SEDATING DRUGS AND MEMORY IMPAIRMENT
The correlation between sleepiness and memory impairment has been established not only in sleep deprivation studies and in patients with sleep disorders but also in studies of the effects of sedative drugs. Because alcohol also is a sedative drug, these studies may help elucidate the mecha nisms of alcohol's actions on the brain. Sedative drugs interact with several different neurotransmitter 1 systems and neurochemicals (i.e., neuropeptides) of the brain that may be involved in regulating sleep and wakefulness and are also involved in memory and learning (Lister et al. 1987;Jones 1994). It is beyond the scope of this article to describe all the systems and neuro chemicals that might be involved; it is a very complex body of research. However, some systems targeted by commonly used drugs that have both sedative and memory impairing effects will be mentioned, owing to some important practical implications discussed later in the article.

GABA and GABA Agonists
Gammaaminobutyric acid (GABA) is one of the major inhibitory neurotransmitters and may promote sleep (Jones 1994). Some sedative drugs, such as benzodiazepines and barbiturates, are GABA agonists (i.e., they mimic or facilitate GABAmediated inhibition of adjacent cells).
GABA agonists also have amnestic effects (Lister 1985) that parallel their seda tive effects as determined by MSLT Roehrs et al. 1994b). Findings that a drug called flumazenil can reverse both benzodiazepineinduced sedation and amne sia (Dorow et al. 1987) support a correlation between sedative and amnestic effects. In contrast, Hommer and colleagues (1993) reported that the two effects are independent. This lack of a sedativeamnestic correlation, however, may be due to the more inconsis tent, selfreportbased assessment of seda tion used in their study.
GABA agonists can interfere with both the stimulus registration phase and the con solidation phase of memory development (Lister 1985;). The extent to which these drugs interfere with memory retrieval is unclear ).

Acetylcholine and Acetylcholine Antagonists
Acetylcholine is a neurotransmitter that is important for maintaining wakefulness and for increasing the firing rate of nerve cells in the cortex. Drugs that are acetyl choline antagonists (i.e., that counteract acetylcholine activity) have both sedative and memoryimpairing effects, as do the GABA agonists (Preston et al. 1989). For example, the acetylcholine antagonists scopolamine and atropine, which are common in overthecounter medications and are used to treat respiratory and gas trointestinal disorders, can disrupt epi sodic and semantic memory functions (Higgins et al. 1989;Preston et al. 1989). These effects on memory are accompa nied by increased sleepiness as deter mined through selfreports.
A role of acetylcholine and acetylcholine antagonists in controlling memory functions is supported by the socalled cholinergic hy pothesis of dementia. This hypothesis suggests that dementia is caused by the degeneration and dysfunction of cholinergic (i.e., acetylcholineusing) neurons. Admini stration of acetylcholine antagonists would correspond to a cholinergic dysfunction.

Histamine and Histamine Antagonists
Histamine also is a neurotransmitter pro moting wakefulness. Histamine antagonists, also called antihistamines, are used for symptomatic treatment of common colds, hay fever, and allergies and are the most common ingredients in overthecounter sleep medications. Antihistamines that readily cross the bloodbrain barrier at clinical doses also increase daytime sleepi ness in a dosedependent manner as meas ured both subjectively and objectively with the MSLT (Nicholson and Stone 1986).
Many studies assessing the effects of antihistamines on psychomotor performance detect impaired performance on the tests (Roth et al. 1987). The time course and dose dependence of the performancedisruptive effects parallel the time course and dose dependence of the antihistamine's sedative effects. The tests used in these studies did not specifically assess cognitive functioning and memory impairment. However, many of the studies demonstrated performance im pairment on the digitsymbol substitution test, 2 which requires some memory abilities.
These examples show that drugs affect ing various neurotransmitter systems can be associated with both sedative and amnestic effects. Some researchers have attempted to reverse the sedative and amnestic effects of a drug affecting one neurotransmitter sys tem by using a drug affecting another neu rotransmitter system (Preston et al. 1989). These socalled crossreversal experiments were not successful, indicating that the different neurotransmitter systems are independent and cannot compensate for each other. However, the lack of cross reversal between agonists and antagonists of different neurotransmitters does not invali date the general hypothesis of a correlation between sedative and amnestic drug effects.

Alcohol's Sedative Effects
Laboratory studies evaluating alcohol's stimulating and sedative effects have found a biphasic response by the test subjects (Pohorecky 1977). At low alco hol doses and while the blood alcohol concentration (BAC) is ascending, alco hol's stimulating effects prevail. In con trast, at high alcohol doses and while the BAC is descending, alcohol primarily has sedative effects. Recently, Petrucelli and colleagues (1994) confirmed the biphasic effects of alcohol using the MSLT method. An alerting effect (i.e., increased sleep latency) was found over the first hour during the ascending phase of the BAC curve and at peak alcohol concentration; subsequently, a sedating effect (i.e., de creased latency) was observed.
Other studies have focused on alcohol's sedative effects throughout the descending phase of the BAC curve and beyond. Alcohol's sedative effects as measured by the MSLT are dose dependent (figure 2; Roehrs et al. /1990Zwyghuizen Doorenbos et al. 1988). With increasing amounts of alcohol (the doses are equiva lent to two to six beers), sleep latency decreases drastically, indicating an increas ing sedative effect. Furthermore, sedation continues for at least 2 hours after the BAC has returned to 0 ).

Alcohol's MemoryImpairing Effects
Alcohol's amnestic effects have been studied extensively. Birnbaum and Parker (1977) found that the degree of amnesia increased with larger doses of alcohol. Most studies report that alcohol impairs the acquisition of new information but does not affect the retrieval of previously memorized information (Mungas et al. 1994). The acquisition impairment occurs both at the attention phase and at the consolidation phase of memory process ing. This amnestic effect has been de scribed as a failure to process information "deeply" or as a "slowing of the process ing rate" (Mungas et al. 1994;Rabbitt and Maylor 1991). Alcohol affects several memory systems. Semantic memory and episodic memory clearly are altered (Mungas et al. 1994). In addition, there are indications that perceptual memory is impaired (Mungas et al. 1994).

The Link Between AlcoholInduced Sedation and Amnesia
So far, no studies have established the correlation between alcohol's sedative and amnestic effects by simultaneously assessing memory impairment and objec tive sleepiness (e.g., with the MSLT). However, several studies provide indirect evidence for such a correlation. Roehrs and colleagues (1989) simulta neously studied alcohol's sedative and performancedisruptive effects. The sub jects received 0.75 gram of alcohol per kilo gram of body weight. The sedative effects of this alcohol dose were measured by the MSLT. Performancedisruptive effects were assessed in two ways: (1) with a divided attention task, in which subjects tracked a moving target on a video screen while simul taneously responding to other stimuli appear ing on the screen, and (2) with an auditory vigilance task, in which subjects detected long tones against the background of shorter tones. The subjects responded more slowly on both tasks but did not omit any respons es, suggesting that alcohol leads to the cognitive slowing described in the sleep loss literature. Subjects with a higher degree of sleepiness tended to show a higher degree of performance impairment. The alcohol effects observed on a divided attention task or an auditory vigilance task likely predict a memoryimpairing effect. This is suggested by studies of the sedative effects of different benzodiazepines that included divided attention and auditory vigilance tasks as well as memory tasks (Roehrs et al. 1994b).
Researchers also have measured alcohol induced memory impairment and selfrated sleepiness. Rabbitt and Maylor (1991) found comparable dose dependence for both mea sures: The increase in memory impairment after larger alcohol doses was paralleled by a similar increase in sedation. The researchers obtained similar results when they analyzed the effects of the benzodiazepine triazolam. Other studies, in contrast, suggest that alco hol's amnestic and sedative effects are inde Sleepiness and Memory Function pendent of each other (Lister et al. 1987). Some of the inconsistencies among the studies may be due to the relatively unreli able selfreports used to assess sedation. Therefore, studies objectively measuring alcoholinduced sedation and concurrently assessing alcohol's amnestic effects are needed to resolve these discrepancies.

Preexisting Sleepiness and Alcohol Induced Performance Impairment
Another strategy to establish a link between sleepiness and performance impairmentand, by inference, memory impairment-is to first manipulate subjects' level of sleepi ness by reducing or extending their TIB for one or more nights. The subjects then receive alcohol, and alcohol's sedative and performancedisruptive effects are assessed (ZwyghuizenDoorenbos et al. 1988;Roehrs et al. , 1994a. Reducing TIB increases the level of sleepiness the following day; the increased sleepiness enhances the sedative and performancedisruptive effects of alcohol (ZwyghuizenDoorenbos et al. 1988). For example, an alcohol dose of 0.4 gram per kilogram of body weight has a lower seda tive effect than an alcohol dose of 0.8 gram per kilogram of body weight if all subjects have had the same TIB the previous night. However, if subjects receiving the low alco hol dose have had only 5 hours TIB for 5 con secutive days and subjects receiving the high alcohol dose have had 8 hours TIB, both alcohol doses have the same sedative effect.
In a similar experiment, simulated driving and psychomotor performance were assessed in subjects who received an alco hol dose of 0.6 gram per kilogram of body weight producing breath ethanol concentra tions of 50 milligrampercent (i.e., half the legal intoxication level in most States) and who had either 8 or 4 hours TIB (Roehrs et al. 1994a). Subjects with 4 hours TIB exhibited significantly greater impairment than subjects with 8 hours TIB. The in creased alcohol effect was not due to dif ferences in alcohol metabolism after reduced TIB, because breath alcohol levels were not affected by the TIB manipulation (ZwyghuizenDoorenbos et al. 1988;Roehrs et al. 1994a).
In contrast, longer TIB reduces the level of sleepiness (i.e., increases alertness) and leads to an attenuation of some of alcohol's effects . Subjects receiving an alcohol dose of 0.75 gram per kilogram of body weight after 8 hours TIB exhibited sedation and performance impairment, compared with subjects receiv ing a placebo after 8 hours TIB. However, after 7 nights of 10 hours TIB, the subjects experienced no effects from the same alcohol dose. Again, breath alcohol levels did not change as a result of the TIB manipulation.

Impact of AlertnessEnhancing Measures
Alcohol's sedative and performance disruptive effects can be attenuated by enhancing the basal level of alertness after alcohol consumption, for example, with daytime naps. colleagues (1989/1990) assessed the effects of a 0.5 gram per kilogram of body weight alcohol dose after the subjects did or did not have a 60minute nap. The nap completely re versed the sedative effect and attenuated the performancedisruptive effects of the alcohol.
Another study examined the capacity of a 60minute nap to reverse the sedative and performancedisruptive effects of alcohol, a benzodiazepine, and an antihistamine (Roehrs et al. 1993). The effectiveness of the nap to reverse the sedative effects of the drugs tested was inversely related to the extent of sedation initially produced by the drugs (figure 3). For example, the benzodiazepine had the strongest sedative effect, which was least reversible by the nap. Alcohol, in contrast, had the smallest sedative effect. This effect was almost completely reversed by the nap.
It is important to note that performance in these studies was assessed using the divided attention and vigilance tasks and therefore did not directly measure memory impairment. Although a thorough evalua tion of alcoholinduced sedation and amnesia is needed in the future, the avail able studies support the hypothesis of a correlation between sedative and amnestic alcohol effects for at least two reasons. First, the alcohol doses used in these stud ies produced sedation levels (as measured by MSLT) comparable with the levels achieved in some of the sedative drug studies that demonstrated amnestic drug effects. Second, the alcohol doses used to assess objectively measured sedation and performance disruption are comparable with those used in studies that demonstrat ed alcohol's amnestic effects without objec tive measures of sedation levels.

MECHANISMS OF ALCOHOL INDUCED SEDATION AND AMNESIA
Alcohol affects some neurotransmitter systems in the same way that sedative drugs do. For example, alcohol facilitates GABAmediated inhibition (i.e., acts as a GABA agonist) and reduces the release of acetylcholine (i.e., acts as an acetylcholine antagonist) (Hoffman and Tabakoff 1985). Consequently, alcohol could mimic the actions of other sedative drugs. Alcohol additionally affects two other neurotrans mitters that regulate sleep and wakefulness. One is serotonin, a neuromodulator of sleep; the other is glutamate, an excitatory neurotransmitter promoting wakefulness. Interaction with these neurotransmitter systems may contribute to alcohol's seda tive effects. The contributions of serotonin and glutamate to memory functions cur rently are being studied extensively.

CONCLUSIONS AND IMPLICATIONS
Independent experiments have shown that alcohol causes memory impairment and that alcohol causes sedation. This article has reviewed information suggesting that the two effects may be linked, that is, that alcohol's amnestic effects are related to its sedative effects. Evidence supporting this hypothesis comes from sleep depriva tion studies in healthy people, studies of patients with sleep disorders, studies of drugs with sedative effects, and studies of the interaction between alcohol's sedative and performancedisruptive effects. However, the sleepinessmemory hypoth esis of alcohol effects has not yet been tested directly by manipulating levels of sleepiness and objectively measuring sedation and memory impairment.
An association between alcohol's seda tive and amnestic effects could have practical implications for both research and clinical issues. For researchers, such an interaction could affect the design of experiments assess ing alcohol's amnestic or performance disruptive effects. For example, researchers would need to control for, or at least docu ment, the amount of sleep their subjects get before the experiment. Similarly, the time of day at which tests are performed could affect study results, given the normal varia tions in people's sleepiness levels across the day. Inattention to these influences could Figure 3 Different sedative drugs differentially decrease sleep latency (i.e., increase sleepiness). All subjects were tested under four conditions: after receiving a placebo, after receiving alcohol (0.6 gram per kilogram of body weight), after receiving the antihistamine diphenhydramine (50 milligrams), and after receiving the benzodiazepine triazolam (0.25 milligram). For each condition, the subjects were tested over a 2-day period. On one day, they took a 1-hour nap 1 hour after drug administration; on the other day, they did not take a nap. The sleep latency for the different conditions is the mean of four measurements taken over the course of the day. Vertical lines indicate the standard error. distort study results and cause inconsistencies when comparing results between studies. From a clinical standpoint, the interaction between alcohol's sedative and amnestic effects would imply that alcohol consump tion combined with any condition or drug producing sleepiness could increase the risk for alcoholinduced memory impairment. For example, subgroups of the general popu lation are known to be sleepier than average. People who shift their sleep schedule fre quently (e.g., night workers or shift work ers) are much sleepier than are people with a regular nighttime sleep schedule. Older people, who experience more fragmented sleep and who are more likely to have undetected sleep disorders, are sleepier than are younger people. In these risk groups, lower alcohol doses than predicted could induce memory impairment. Younger people who periodically sleep less (e.g., when studying for exams) similarly may experience memory problems after consum ing alcohol in amounts they usually tolerate.
In addition, drugs with sedative effects could lead to amnesia when combined with alcohol, even at doses normally considered safe. Benzodiazepines, which often are used for patients undergoing alcoholism treatment, could contribute to amnesia if the patients relapse. A brief report in the late 1980's described three clinical cases of global amnesia (i.e., total amnesia for recent events) associated with the concur rent use of the benzodiazepine triazolam and alcohol (Morris and Estes 1987). Many overthecounter cold medications and many antidepressants have anticholin ergic and/or antihistaminic ingredients that could contribute to amnesia after alcohol consumption, even in social drinkers. In addition, recovering alcoholics with coex isting depression often are treated with antidepressants. If a relapse occurs, the sedating side effects of these medications could increase the risk for amnesia. ■